Abstract
Chronification of inflammation is the process that lies at the basis of several human diseases that make up to 80% of morbidity and mortality worldwide. It can also explain a great deal of processes related to aging. Atherosclerosis is an example of the most important chronic inflammatory pathology in terms of public health impact. Atherogenesis is based on the inflammatory response of the innate immunity arising locally or focally. The main trigger for this response appears to be modified low-density lipoprotein (LDL), although other factors may also play a role. With the quick resolution of inflammation, atherosclerotic changes in the arterial wall do not occur. However, a violation of the innate immunity response can lead to chronification of local inflammation and, as a result, to atherosclerotic lesion formation. In this review, we discuss possible mechanisms of the impaired immune response with a special focus on mitochondrial dysfunction. Some mitochondrial dysfunctions may be due to mutations in mitochondrial DNA. Several mitochondrial DNA mutations leading to defective mitophagy have been identified. The regulatory role of mitophagy in the immune response has been shown in recent studies. We suggest that defective mitophagy promoted by mutations in mitochondrial DNA can cause innate immunity disorders leading to chronification of inflammation.
Highlights
Chronification of inflammation is relevant to many human disorders and a subject of active current research that aims to answer the numerous questions remaining to date
We hereby present the hypothesis that defective mitophagy caused by mitochondrial DNA (mtDNA) mutations plays a central role in the transition of normal inflammatory reaction of the innate immunity to chronic inflammation, which can be observed in atherosclerosis
The signaling induced by the interaction of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) with innate immune cell receptors triggers the activation of nuclear factor (NF)-κB-mediated production and secretion of pro-inflammatory cytokines, which further leads to the recruitment of the effector cells and their inflammatory action in response to infection [41,50]
Summary
Chronification of inflammation is relevant to many human disorders and a subject of active current research that aims to answer the numerous questions remaining to date. We discuss the role of the immune response disturbance at the level of mitochondrial dysfunction, in particular, defective mitophagy. Stages of the disease development are characterized by prominent local differences between the adjacent areas of the arterial wall in terms of inflammatory activation. Comparison of such areas may reveal the cells, molecules and signaling pathways that are responsible for inflammation chronification. We hereby present the hypothesis that defective mitophagy (clearance of dysfunctional mitochondria) caused by mtDNA mutations plays a central role in the transition of normal inflammatory reaction of the innate immunity to chronic inflammation, which can be observed in atherosclerosis
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